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Updated: Jan 25, 2026

Genetic and Biochemical Approaches for In Vivo and In Vitro Assessment of Protein Oligomerization: The Ryanodine Receptor Case Study
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Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse

Samantha C Salvage1,2, Esther M Gallant3, Nicole A Beard4

  • 1Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.

Journal of Cell Science
|April 28, 2019
PubMed

Insights

The RyR2-P2328S mutation significantly alters cardiac ryanodine receptor Ca2+ channel activity, increasing channel opening at low Ca2+ levels. This dysfunction contributes to dangerous heart arrhythmias like CPVT and AF.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Ion Channel Biophysics

Background:

  • Mutations in the cardiac ryanodine receptor Ca2+ release channel (RyR2) are linked to life-threatening ventricular arrhythmias and atrial fibrillation (AF).
  • The RyR2-P2328S mutation specifically causes catecholaminergic polymorphic ventricular tachycardia (CPVT) and AF in mice with homozygous RyR2 mutations (RyR2S/S).

Purpose of the Study:

  • To investigate the functional consequences of the P2328S mutation on RyR2 channel activity.
  • To determine how the P2328S mutation affects Ca2+ activation and inactivation properties of the RyR2 channel.

Main Methods:

  • Electrophysiological analysis of wild-type (WT) and P2328S RyR2 channels.
  • Measurement of channel activity at varying cytoplasmic Ca2+ concentrations (1 mM and 1 µM).
  • Determination of half-maximal activation (AC50) and inactivation (IC50) concentrations for Ca2+.

Main Results:

  • P2328S RyR2 channels exhibit significantly increased activity compared to WT RyR2 at low cytoplasmic Ca2+ (1 µM).
  • The mutation caused a >10-fold shift in AC50 for Ca2+ activation and a >1000-fold shift in IC50 for inactivation, with inactivation occurring at systolic Ca2+ levels.
  • These functional changes were not associated with altered sub-conductance activity, phosphorylation at S2806/S2814, or FKBP12 binding.

Conclusions:

  • The P2328S mutation in RyR2 leads to altered Ca2+ handling by the channel, promoting arrhythmogenic activity.
  • These channel dysfunction mechanisms correlate with observed Ca2+ dysregulation in myocytes and the CPVT/AF phenotypes in RyR2S/S mice.
Keywords:
Atrial fibrillationCatecholaminergic polymorphic ventricular tachycardiaCytoplasmic Ca2+ activationCytoplasmic Ca2+ inactivationFKBPP2328S-RyR2 mouseRyR2 P2328S ion channel

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